This proposal describes a 5-year training program for the development of an academic career in the field of cancer genetics. The candidate completed his M.D at the Stanford University School of Medicine, as well as a highly productive Ph.D. in the Department of Genetics at Stanford. He spent several years co-founding a systems biology company, Ingenuity Systems, before returning to medicine to complete a residency program in the Department of Dermatology at the University of California, San Francisco. As a young investigator in the department, he has authored two original research articles illuminating the molecular progression of squamous cell carcinomas. Through the proposed training program, the candidate will expand upon his scientific skills to become an independent investigator developing new genomic approaches to cancer genetics. He will meet these goals through coursework, participation in conferences and seminar series, national presentations, and steerage of a mentored research project. Dr. Boris Bastian will mentor the candidate's scientific development. Dr. Bastian is a nationally recognized expert in study of somatic abnormalities in skin cancers and has characterized key underlying mutations in cutaneous (KIT) and uveal (GNAQ and GNA11) melanoma. The advisory committee will consist of a national expert in Notch receptor structure and function in cancer (Dr. Jon C. Aster, MD, PhD, Professor of Pathology, Brigham and Women's Hospital), a leading epigeneticist (Dr. Joseph Costello, MD, PhD, Associate Professor, UCSF), and a leader in cancer genomics and epigenomics (Dr. Joe W. Gray, PhD, Gordon Moore Professor and Chair, Biomedical Engineering, OHSU). Research will focus on the newly discovered role of the Notch receptor and downstream signaling pathway in epithelial tumorigenesis. Recent studies, including one led by the candidate, have revealed frequent somatic mutation of Notch receptors in squamous cell carcinomas of the skin, head-and-neck, and lung. Because Notch also activates hematologic cancers, this work delineates the first known tissue-specific, bifunctional tumor suppressor/oncogene. The research project will examine other epithelial cancers for somatic Notch mutation and develop fine-mapped expression signatures to explore the epigenetic context of Notch function. Next-generation sequencing of DNA and transcriptome (RNA) will be employed. The aggregate data will provide a detailed portrait of the state of a critical pathway across a series of important solid cancers. The proposed training program draws on the combined resources of the UCSF Cancer Center and the UCSF Department of Dermatology. This will provide an ideal setting for the candidate's maturation into an independent investigator.